Abstract
BackgroundSickle cell anemia (SCA), one of most prevalent monogenic diseases worldwide, is caused by a glutamic acid to valine substitution on the beta globin protein of hemoglobin, which leads to hemolytic anemia. Hydroxyurea, the only disease-modifying therapy approved by the Food and Drug Administration for SCA, has proven to be a viable therapeutic option for SCA patients in resource-rich settings, given clinical improvements experienced while taking the medication and its once-daily oral dosing. Significant studies have demonstrated its safety and clinical efficacy among children and adults in developed countries. In Sub-Saharan Africa, however, the risk of malaria, hematologic toxicities, and safety of hydroxyurea in children with SCA living in malaria-endemic areas are unknown.ObjectivesStudy objectives include determining the incidence of malaria in SCA patients taking hydroxyurea versus placebo; establishing the frequency of hematologic toxicities and adverse events (AEs) in children with SCA treated with hydroxyurea versus placebo; and defining the relationships between hydroxyurea treatment and fetal hemoglobin, soluble intracellular adhesion molecule-1, and nitric oxide levels, and between levels of these factors and risk of subsequent malaria.MethodsNovel use Of Hydroxyurea in an African Region with Malaria (NOHARM, NCT01976416) is a prospective, randomized, placebo-controlled, double-blinded phase III trial to compare risk of malaria with oral hydroxyurea versus placebo. Children will be recruited from the Mulago Hospital Sickle Cell Clinic in Kampala, Uganda.ResultsTwo hundred Ugandan children aged between 1.00 and 3.99 years with confirmed SCA will be randomized into treatment groups by order of entry in the study, based on a predetermined blinded randomization list. The primary outcome of the trial is malaria incidence in the 2 study groups, defined as episodes of clinical malaria occurring over the 1-year randomized study treatment period.ConclusionNOHARM will be the first prospective randomized, placebo-controlled clinical trial investigating the use of hydroxyurea for children with SCA in a malaria-endemic region within Africa. The results of this trial have the potential to significantly advance understanding of how to safely and effectively use hydroxyurea in children with SCA in malaria-endemic areas.Trial RegistrationClinicaltrials.gov NCT01976416; https://clinicaltrials.gov/ct2/show/NCT01976416 (Archived by WebCite at http://www.webcitation.org/6hmoilZnp)
Highlights
Background and RationaleSickle cell anemia (SCA) is a genetic blood disorder where sickling of red blood cells, due to a genetic alteration in hemoglobin, leads to chronic hemolysis, organ damage, vaso-occlusive events, and other potentially life-threatening complications [1]
The primary outcome of the trial is malaria incidence in the 2 study groups, defined as episodes of clinical malaria occurring over the 1-year randomized study treatment period
NOHARM will be the first prospective randomized, placebo-controlled clinical trial investigating the use of hydroxyurea for children with SCA in a malaria-endemic region within Africa
Summary
Sickle cell anemia (SCA) is a genetic blood disorder where sickling of red blood cells, due to a genetic alteration in hemoglobin, leads to chronic hemolysis, organ damage, vaso-occlusive events, and other potentially life-threatening complications [1]. It is acquired in an autosomal recessive fashion and is most prevalent in Africa, where over 230,000 babies with SCA are born annually [2]. Interventions such as prophylactic penicillin, pneumococcal immunizations, newborn screening programs, and the availability of hydroxyurea have significantly decreased SCA-associated morbidity and mortality, thereby leading to improved survival into adulthood. In Sub-Saharan Africa, the risk of malaria, hematologic toxicities, and safety of hydroxyurea in children with SCA living in malaria-endemic areas are unknown
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